Synthesis, characterization and antibacterial activities of N-tert-butoxycarbonyl-thiazolidine carboxylic acid

Article abstract of DOI:10.1039/c4ra15284k

A possible mechanism of dynamic kinetic resolution by the formation of N-tert-butoxycarbonyl-thiazolidine carboxylic acid was proposed and validated by a quantitative density functional theoretical calculation according to Curtin-Hammett principle. Such a

Full text of DOI:10.1039/c4ra15284k

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Synthesis, Characterization and Antibacterial Activities of
N-tert-Butoxycarbonyl-Thiazolidine Carboxylic Acid
Zhong-Cheng Song a,b, Gao-Yuan Mab and Hai-Liang Zhua, b*
a School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China, 310053
b School of Life Sciences, Nanjing University, Nanjing, Jiangsu, P. R. China, 210093
*Corresponding Author, E-mail: zhuhl@nju.edu.cn; Fax: +86-25- 83592672; Tel: +86-25-83592672
The mechanism of dynamic kinetic resolution by the formation of N-Boc-TCAs was proposed and
a qualitative explanation was interpretated according to Curtin-Hammett principle. Such a
mechanism of action of a nucleophilic substitution reaction through an intramolecular hydrogen
bonding could be widely applied in the organic syntheses of particular enantiomer.

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ARTICLE TYPE
Synthesis, Characterization and Antibacterial Activities of N-tert-Butoxycarbonyl-Thiazolidine
Carboxylic Acid
Zhong-Cheng Song a,b, Gao-Yuan Mab and Hai-Liang Zhua, b*
a School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China, 310053
b School of Life Sciences, Nanjing University, Nanjing, Jiangsu, P. R. China, 210093
5
*Corresponding Author, Eꢀmail: zhuhl@nju.edu.cn; Fax: +86ꢀ25ꢀ 83592672; Tel: +86ꢀ25ꢀ83592672
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A
possible
mechanism
of
dynamic
kinetic
resolution
by
the
formation
of
10 Nꢀtertꢀbutoxycarbonylꢀthiazolidine carboxylic acid was proposed and validated by a quantitative density
functional theoretical calculation according to CurtinꢀHammett principle. Such a mechanism of action
of a nucleophilic substitution reaction through an intramolecular hydrogen bonding could be widely
applied in the organic syntheses of particular enantiomer. Antibacterial activities showed that most of the
Nꢀtertꢀbutoxycarbonylꢀ(2R)ꢀarylthiazolidineꢀ(4R)ꢀcarboxylic
15 antibacterial activities against the four
(2RS)ꢀarylthiazolidineꢀ(4R)ꢀcarboxylic acid derivatives.
acid
bacterial
derivatives
strains
exhibited
than
better
related
important natural products, such as penicillin and biotin9ꢀ10
Therefore, thiazolidine derivatives have become especially
noteworthy in recent years11ꢀ13
In this paper, because of the wide application of the
45 tertꢀbutoxycarbonyl(Boc) protecting group, under the guidance of
the CurtinꢀHammett principle, we synthesized a series of
.
1
Introduction
.
Kinetic resolution has long been recognized as an effective tool
for the preparation of enantiomerically pure compounds for fine
20 chemicals (i.e. agrochemicals and pharmaceuticals) and material
science (i.e. liquid crystals and polymers)1ꢀ2. However, the main
drawback of the conventional kinetic resolution was that the
obtained maximum theoretical yield of one stereoisomer of the
starting material or product could be 50%, which was too low to
25 allow a positive economic and environmental balance for such
transformations3. To overcome this limitation, of all the strategies
that allow the transformation of both enantiomers of a racemate
into a single enantiomer of the product, dynamic kinetic
resolution (DKR) has been the focus of many studies in recent
30 years. With DKR, the reactant isomers must be in rapid
equilibrium, making removal of one isomer the rate determining
step, and the product could be obtained optically pure in 100%
NꢀBocꢀ(2R)ꢀarylꢀthiazolidineꢀ(4R)ꢀcarboxylic
(NꢀBocꢀTCAs) compounds using the control factors of
intramolecular hydrogen bond inducedꢀstericꢀhindrance,
50 combined with dynamic kinetic resolution14ꢀ18
The
acids
.
corresponding reaction mechanism and the corresponding
theoretical explanation were proposed. In order to compare the
differences of antibacterial activities of NꢀBocꢀTCAs and TCAs,
we tested the antibacterial activities of them against the four
55 bacteria, Grampositive (Bacillus subtilis ATCC 6633 and
Staphylococcus aureus ATCC 6538) and Gramꢀnegative
(Pseudomonas aeruginosa ATCC 13525 and Escherichia coli
ATCC 35218), which often caused infection in burned patients.
yield (Figure 1)4ꢀ5
.
2
Results and Discussion
60 2.1 Chemistry
The synthetic route to NꢀBocꢀTCAs (13ꢀ24) is shown in Scheme
1. The syntheses of TCAs (1-12) were carried out using our
previous literature method16, by reaction of commercially
available aromatic aldehyde and Lꢀcysteine in the presence of
65 ethanol with excellent yield. Treatment of 1-12 with
tꢀbutyloxycarbonyl anhydride ((Boc)2O) yielded NꢀBocꢀTCAs
(13ꢀ24)16. The structures of the synthesized compounds (1ꢀ24)
were listed in Table 1. All of the synthetic compounds were
characterized by spectroscopic data, which were full accordance
70 with their structures.
35 Figure 1. Schematic representation of a dynamic kinetic resolution
(DKR).
The steric course of the reaction between Lꢀcysteine and
aldehydes deserved much attention because this reaction had been
implicated in several biochemical processes6ꢀ8. An analogous
40 condensation reaction constituted the first step in the syntheses of
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Scheme 1. Syntheses of 2ꢀarylꢀNꢀBocꢀ1,3ꢀthiazolidine acid (TCAs)
13ꢀ24.
Table 1. The structures of the synthesized compounds (1ꢀ24)
20
Figure 3. 1H NMR of the compound 22
2.2 Crystal structure Analysis
In order to study the absolute structure of the product, we
cultured some of the crystal structure of NꢀBOCꢀTCAs which are
helpful to explain the mechanism of formation of NꢀBOCꢀTCAs.
25 Fortunately, Xꢀray singleꢀcrystal diffraction data for compounds
13, 15, 21 and 22 were collected on a Nonius CAD4
diffractometer equipped with graphiteꢀmonochromatized MoKα
Table2. selected bond lengths (Å), bond angles (°) and torsion angles(°)
for compounds 13, 15, 21 and 22.
Compounds
R1
H
H
OMe
H
H
H
Cl
H
H
Br
H
R2
H
H
H
H
F
H
H
Cl
H
H
H
H
R3
H
OH
H
OMe
H
F
H
H
Cl
H
Br
H
R4
H
H
H
H
H
H
H
H
H
H
H
F
R5
H
H
H
H
H
H
H
H
H
H
H
H
1
2
13
14
15
16
17
18
19
20
21
22
23
24
3
4
5
6
7
8
9
13
15
21
22
H(7)ꢀꢀꢀ H(8)#1
H(7)ꢀꢀꢀ C(10)#1
H(8)ꢀꢀꢀ C(6)#1
3.418
4.227
4.444
116.5
103.5
110.8
108.6
108.6
108.6
105.7
114.2
111.1
108.6
108.6
108.6
3.550
4.447
4.262
116.2
103.3
113.6
107.8
107.8
107.8
105.5
114.0
109.7
109.2
109.2
109.2
3.456
4.247
4.444
117.2
102.2
109.2
109.3
109.3
109.3
106.6
115.7
109.6
108.2
108.2
108.2
3.481
4.278
4.397
112.9
107.6
101.9
111.3
111.3
111.3
106.1
113.3
118.3
106.1
106.1
106.1
10
11
12
OH
N(1)ꢀC(7)ꢀC(6)
N(1)ꢀC(7)ꢀS(1)
C(6)ꢀC(7)ꢀS(1)
C(6)ꢀC(7)ꢀH(7)
N(1)ꢀC(7)ꢀ H(7)
S(1)ꢀC(7)ꢀ H(7)
N(1)ꢀC(8)ꢀC(9)
N(1)ꢀC(8)ꢀC(10)
C(9)ꢀC(8)ꢀC(10)
C(9)ꢀC(8)ꢀH(8)
N(1)ꢀC(8)ꢀ H(8)
C(10)ꢀC(8)ꢀ H(8)
5
Figure 2. 1H NMR of the compound 10
Φ1[C(1)ꢀC(2)ꢀC(3)ꢀC
(4)ꢀC(5)ꢀC(6)] #2
Φ2[C(7)ꢀN(1)ꢀC(8)ꢀC
(9)ꢀS(1)] #2
0.0059
0.0049
0.0052 0.0097
0.1972 0.2035
From the 1H NMR results, the unprotected TCA compounds
2ꢀarylꢀ1,3ꢀthiazolidine acids were obtained two diastereomers.
0.2078
98.8
0.2003
101.2
The ratio of the most two diastereomers is nearly to 1:1. For
#3
1
Φ1∩Φ2
77.2
69.6
10 example, from the Figure 2 and Figure 3, the H NMR of the
new born 4ꢀposition H (CH) of the thiazolidine ring in the 30 #1 represents the calculate value of space distance; #2 represents the
compound 10 has two peaks and the chemical shift values are
5.90 and 5.72. However, the 1H NMR of the 4ꢀposition H (CH) of
the thiazolidine ring in the compound 22 only has one single peak
15 and the chemical shift value is 6.12. It suggested that the
unprotected TCA compounds 2ꢀarylꢀ1,3ꢀthiazolidine acids have
two diastereomers and the protected TCA compound
2ꢀarylꢀNꢀBocꢀ1,3ꢀthiazolidine acid is single chiral isomer.
mean deviation distances from the surface; #3 represents the dihedral
angle of two ring surfaces Φ1 and Φ2.
(λ = 0.71073 Å) radiation. The program CAD4 software was
used for data collection and cell refinement. Data reduction was
35 solved by XCAD4 program. Structure was solved by direct
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methods using the SHELXS program of the SHELXTL package
and refined by fullꢀmatrix leastꢀsquares methods with SHELXL19.
The selected bond distances, bond angles and torsion angles are
given in Table 2. Crystal structure data of compounds 13, 15, 21
and 22 are given in Table 3. Figure 4, Figure 5, Figure 6 and
Figure 7 gave typically perspective view of compounds 13, 15,
21 and 22 with the atomic labeling system, respectively. Further
details of the crystal structure investigations may be obtained
5
from
the
Fachinformationszentrum
Karlsruhe,
76344
10 EggensteinꢀLeopoldshafen, Germany (fax: (+49) 7247ꢀ808ꢀ666;
eꢀmail: crysdata@fizꢀkarlsruhe.de) on quoting the deposition
numbers CSDꢀ760948, ꢀ703635, ꢀ703637, and ꢀ703638.
15 Figure 4. Molecular structure (thermal ellipsoids at the 35% probability
level) of compound 13.
Table 3. Crystal structure data of compounds 13, 15, 21 and 22.
13 15 21
C15H19NO4S C16H21NO5S C15H18ClNO4S
Compound
Formula
Mr
22
C15H18BrNO4S
388.27
0.20×0.10× 0.10
Monoclinic
P21
10.485(2)
6.6020(13)
12.803(3)
90.00
103.81(3)
90.00
309.37
0.30×0.20× 0.10
Monoclinic
P21
339.40
0.30×0.20× 0.10
Orthorhombic
P212121
343.81
0.30×0.20× 0.10
Monoclinic
P21
Crystal size (mm3)
Crystal system
Space group
a (Å)
10.308(2)
6.3790(13)
12.174(2)
90.00
6.4240(13)
10.255(2)
27.064(5)
90.00
6.4600(13)
10.641(2)
12.411(3)
90.00
b (Å)
c (Å)
α (οC)
β (οC)
100.71(3)
90.00
90.00
90.00
94.52(3)
90.00
γ (οC)
V (Å3)
786.6(3)
2
1782.9(6)
4
850.5(3)
2
860.6(3)
2
1.498
Z
Dc (g/cm3)
1.306
1.264
1.343
ꢀ
(mmꢀ1)
0.220
0.204
0.363
2.525
F (000)
328
720
1.50/25.16
0/7, 0/12, 0/32
360
396
θ
range (ο)
1.70/25.26
ꢀ12/12, 0/7, 0/14
1.65 / 25.26
ꢀ7/7, 0/12, 0/14
1.64/ 25.16
ꢀ12/12, 0/7, 0/15
Index range (h, k, l)
Reflections collected /
unique
1660 / 1571
0.0406
1887 / 1648
0.0248
1638 / 1462
0.0461
1687 / 1459
0.0362
R(int)
Observed reflections I
1348
1317
1363
1281
>2σ(I)
Min. and max.
transmission
0.9646 and
0.8989
0.9783 and 0.9369
1571 / 49 / 190
0.9798 and 0.9412
1887/ 43 / 207
0.7863 and 0.6321
1687 / 61 / 203
Data/restraints/param
eters
1638 / 78 / 185
Goodnessꢀofꢀfit on F2
R1, wR2 [I >2σ (I)]
R1, wR2
1.005
0.0524/0.1273
0.0674/0.1558
1.092
0.0726/0.1909
0.0998/0.2200
1.084
0.0619 / 0.1453
0.0761 / 0.1592
1.036
0.0525/0.1233
0.0728/0.1363
Absolute structure
parameter
0.0(2)
0.1(3)
ꢀ0.09(19)
ꢀ0.02(2)
Large diff. peak and
hole (e Åꢀ3)
0.354/ꢀ0.228
0.428 / ꢀ0.387
0.435 / ꢀ0.368
0.383 and ꢀ0.480
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could see that the surface mean deviation angles of
benzene ring C1ꢀC2ꢀC3ꢀC4ꢀC5ꢀC6 defined as Φ1 and
ring C7ꢀN1ꢀC8ꢀC9ꢀS1 defined as Φ2 were 0.0060 Å
and 0.2079 Å respectively. In addition, the dihedral
angle of surfaces Φ1 and Φ2 was 98.8°, demonstrating
that the two surfaces was almost in a vertical position,
which arranged in the structure of stable
conformations, avoiding a large steric effect of the
substituents between the benzene ring and the newly
formed fiveꢀmembered ring. The space distance length
of H7ꢀꢀꢀ H8 was 3.418 Å by calculating value, while
that of H7ꢀꢀꢀC10 was 4.227 Å, which showed that the
space distance length of the latter is longer than that of
the former, therefore, atom H7 and atom C10 were
indicated in the opposite position of ring Φ2. By
comparing the bond angles with C7 and C8 as the
centers (see Table 2), every bond angle was almost
near to 109.5°, which demonstrated that C7 and C8
were sp3ꢀhybrid. Because of H7 and C10 on both side
of ring Φ2, H7 and H8 were on same side of ring Φ2.
From the starting structure of compound Lꢀcysteine,
the configuration of C8 of compound 13 was
(R)ꢀconfiguration. Therefore, the configuration of C7
of compound 13 also was (R)ꢀconfiguration according
to IUPAC nomenclature. Furthermore, from Table 3,
we can see that the Flack parameter of crystal 13 is
0.0(2). Consequently to literature, compound 13 can
be showed a (2R,4R)ꢀconfiguration as a single chiral
isomer.20ꢀ22 Likewise, from Table 3, Figure 5, Figure
6 and Figure 7, the crystal structures of the other three
compounds 15, 21 and 22 were analyzed based on the
same consideration. The result is that compounds 15,
21 and 22 is (2R,4R)ꢀconfiguration as a single chiral
isomer respectively.
Figure 5. Molecular structure (thermal ellipsoids at the 35%
probability level) of compound 15.
Figure 6. Molecular structure (thermal ellipsoids at the 35%
probability level) of compound 21.
2.3 Mechanism of reaction
To study the cause of the single chiral isomer, we
referred corresponding mechanism of reaction of
NꢀBocꢀTCAs. As showed in Figure 8, the reaction of
(R)ꢀcysteine and aryl aldehyde produced the Schiff
base intermediate I, which had two epimers (Z)-II and
(E)-II. (2S,4R)-III and (2R,4R)-III were generated
through intramolecular hydrogen bond activation
respectively. (2S,4R)-III and (2R,4R)-III were
alkalified and then (2S,4R)-IV and (2R,4R)-IV were
also formed through intramolecular hydrogen bonding,
respectively. Theoretically, (2S,4R)-V and (2R,4R)-V
should be rapidly equilibrated into an approximately
1:1 mixture like (2S,4R)-III and (2R,4R)-III.
However, one pair of electrons of N atom of
(2S,4R)ꢀIV or (2R,4R)ꢀIV attacked C atom of the
carbonyl of diꢀtertꢀbutyl carbonate through an SN2
substitution reaction. This N atom was also a fictitious
chiral center. Because of sterical intramolecular
hydrogen bond activation, one pair of electrons of N
atom of (2S,4R)ꢀIV or (2R,4R)ꢀIV must assault C
atom of the carbonyl of diꢀtertꢀbutyl carbonate from
the back of the ring Φ2. Nevertheless, the sterically
Figure 7. Molecular structure (thermal ellipsoids at the 35%
probability level) of compound 22.
From Table 2 and Figure 4, for compound 13, we
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crowded effect of suprafacial aryl of (2S,4R)-IV was
(4R)ꢀcarboxylic acid as the single product was
larger than that of different aryl surface of (2R,4R)-IV.
Obviously, the rate of step (2R,4R)-IV → (2R,4R)-V
should be much faster than that of step (2S,4R)-IV →
(2S,4R)-V and the rate constants named k2 and k1
respectively. So, k2 was much larger than k1 (k2 >> k1).
Because all the reactions were synthesized at room
temperature, the reaction rate was assumed to be
controlled by dynamic kinetic resolution effect.
obtained because of dynamic kinetic resolution effect.
A corresponding qualitative explanation from the
theory was interpretated according to dynamic kinetic
resolution and CurtinꢀHammett principle combined
with above reaction mechanism, see Figure 94ꢀ5. At
first, we found the potential energy was very low in
the
(2S,4R)-IV↔(2S,4R)-III↔(Z)-II↔Schiff
intermediate
transformation
process
of
intermediate
base
Therefore, the reaction rate of (2S,4R)-V
→
I↔(E)-II↔(2R,4R)-III↔(2R,4R)-IV
(2S,4R)-IV → (2S,4R)-III → (Z)-II → Schiff base
intermediate I → (E)-II → (2R,4R)-III → (2R,4R)-IV
→ (2R,4R)-V should be much faster than that of
inverse sequence. As a result, (2S,4R)ꢀV was almost
(Figure 8 and Figure 9). So, the above transformation
process could be simplified (2S,4R)-IV↔(2R,4R)-IV
(Figure 10).
converted
into
(2R,4R)-V.
As
acquired,
(2R)ꢀarylꢀ3ꢀtertꢀbutoxycarbonylꢀ1,3ꢀthiazolidineꢀ
HS
HS
O
H
H
+
H
Ar
(R)
(R)
H
Schiff base intermediate I
N
COOH
C
H2N
COOH
Ar
H
H
S
H
S
Ar
H
O
H
O
O
O
Ar
N (R)
H
N (R)
(E)-II
(Z)-II
H
H
H
O
H
O
O
S
S
H
H
N(R)
H
(2S, 4R)-III
N(R)
Ar
(2R, 4R)-III
O
H
(R)
(S)
Ar
H
H
OH
OH
H
H
O
S
O
H
S
N(R)
H
O
(R)
(2S, 4R)-IV
N(R)
Ar
(2
R, 4R)-IV
O
(S)
Ar
H
SN2
O
SN2
O
H
O
O
O
O
k2 (k2 >> k1)
k1
O
O
O
O
H
O
S
(R)
O
H
O
H
S
N(R)
H
O
H
(2 , 4 ) V
R R -
N(R)
Ar
(2S, 4R)-V
O
H
(S)
Ar
O
O
O
Figure 8. The proposed mechanism of formation of compounds 13ꢀ24.
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Figure 9. CurtinꢀHammett mechanism of 2ꢀarylꢀNꢀBocꢀ1,3ꢀthiazolidine derivatives. ꢁG1‡ represents the Gibbs free potential energy
of (2S,4R)ꢀIV→(2S,4R)ꢀV, ꢁG2‡ represents the Gibbs free potential energy of (2R,4R)ꢀIV→(2R,4R)ꢀV; ꢁGο represents the Gibbs
free potential energy of (2S,4R)ꢀIV→(2R,4R)ꢀIV.
Figure 10. Simplified reaction mechanism of 2ꢀarylꢀNꢀBocꢀ1,3ꢀthiazolidine derivatives
effects were addressed by the polarizable continuum
According to the relationship between equilibrium
constant and Gibbs free energy, we can get Equation
1:
model using the integral equation formalism variant
(IEFPCM) with UAHF radii26. The structures of
transition state are depicted in Figure 11 and Figure
12.
Equation 1. The relationship between equilibrium constant
and Gibbs free energy.
In the theoretical model, the Ar group was simplified
to Ph, and the (Boc)2O was simplified to (MeOCO)2O.
All calculations were performed by Gaussian0323
software suite. Geometries of intermediates and
transition states were fully optimized without any
constraints using B3LYP24ꢀ25 functional with
6ꢀ31+G(d) basis set. All geometries were confirmed
by frequency analysis in which an intermediate has no
negative frequency and a transition state has only one
negative frequency corresponding to the reaction
coordinate. The thermodynamic corrections for Gibbs
free energy at 298.15 K were calculated at the same
level of geometrical optimizations. Single point
calculations were conducted using B3LYP functional
with a larger basis set, 6ꢀ311+G(2d,p). The solvent
Figure 11. The structure of transition state leading to
(2S,4R)-V. Key bond lengths were shown in the unit of
Angstrom.
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to CurtinꢀHammett principle. Such a mechanism of
anucleophilic substitution reaction through an
intramolecular hydrogen bonding could be widely
applied in the organic syntheses of special
enantiomers. Antibacterial activities showed that most
of the NꢀBocꢀTCAs exhibited better antibacterial
activities against Grampositive bacteria(B. subtilis and
S. aureus) and Gramꢀnegative bacteria(P. aeruginosa
and E. coli) than relative TCAs.
Table 4. IC50 values of the synthesized TCAs 1ꢀ12 and
NꢀBocꢀTCAs 13ꢀ24 against the four bacteria.
IC50s(ꢀg/mL)
Gram positive
Gram negative
Compound
B.
S.
P.
E.
subtilis aureus aeruginosa
coli
1
3.125
25
12.5
>50
>50
25
25
>50
6.25
>50
6.25
25
Figure 12. The structure of transition state leading to
(2R,4R)-V. Key bond lengths were shown in the unit of
Angstrom.
2
3
6.25
12.5
3.125
6.25
12.5
6.25
12.5
25
12.5
25
12.5
>50
‡
‡
According to the calculate results, ꢁG1 , ꢁG2 and
ꢁGο were 174.7 kJ/mol, 149.5 kJ/mol and 3.3 kJ/mol,
respectively. All data were substituted to Equation 1,
and the value of [(2R,4R)-V]/[(2S,4R)-V] was 6705.
The percentage of (2R,4R)-V accounted the entire
system ((2R,4R)-V and(2S,4R)-V) of 99.99%.
4
5
6.25
12.5
12.5
12.5
12.5
25
1.562
3.125
12.5
6.25
12.5
25
6
7
25
Therefore, the yield of (2R,4R)ꢀV is much more than
that of (2S,4R)ꢀV in the case of such high steric
hindrance potential energy. As the above analysis, the
single chiral isomer 2ꢀarylꢀNꢀBocꢀthiazolidine
derivatives were gained under the control factors of
8
12.5
50
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
50
25
25
12.5
1.562
0.78
0.39
0.78
0.39
0.195
0.78
0.78
0.39
0.78
0.78
0.39
0.195
25
intramolecular
hydrogen
bond
inducedꢀstericꢀhindrance.
3.125
3.125
0.39
1.562
3.125
0.39
1.562
1.562
0.78
1.562
1.562
3.125
0.39
6.25
0.78
3.125
1.562
1.562
0.39
0.78
1.562
0.78
0.78
3.125
3.125
0.39
12.5
0.39
0.78
0.39
0.78
1.562
1.562
0.78
0.39
1.562
1.562
0.39
0.78
2.4 In vitro antibacterial assay
The activities of synthesized NꢀBocꢀTCAs were tested
against Grampositive (Bacillus subtilis ATCC 6633 (B.
subtilis) and Staphylococcus aureus ATCC 6538 (S.
aureus))
and
Gramꢀnegative
(Pseudomonas
aeruginosa ATCC 13525 (P. aeruginosa) and
Escherichia coli ATCC 35218 (E. coli)), which often
caused infection in burned patients by MTT method.
The IC50s of the compounds against four bacteria are
presented in Table 4. Also included are the activities
of reference compounds Kanamycin G and Penicillin
B. Antibacterial activities showed that most of the
NꢀBocꢀTCAs exhibited better antibacterial activities
against the four bacterial strains than relative TCAs.
3
Conclusions
Kanamycin
In summary, the mechanism of dynamic kinetic
resolution by the formation of NꢀBocꢀTCAs was
proposed and a quantitative theoretical calculation was
interpretated by Gaussian03 software suite according
0.39
1.562
1.562
3.125
6.25
3.125
6.25
G
Penicillin
B
1.562
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4
Experimental Section
4.1 Chemistry
5.51 (s, 0.4H), 4.20ꢀ4.16 (m, 0.6H), 3.92ꢀ3.87 (m,
0.4H), 3.37ꢀ3.26 (m, 1H), 3.13ꢀ3.05 (m, 1H). MS (ESI)
m/z 226 (Mꢀ1). Anal. Calcd for C10H10FNO2S: C,
52.85; H, 4.44; N, 6.16; Found: C, 52.66; H, 4.46; N,
6.14.
All the reagents and solvents used were analytical
reagent grade or were purified by standard methods
before use. ESI mass spectra were obtained on a
Mariner System 5304 mass spectrometer, and 1H
NMR was recorded at DPX300 in DMSOꢀd6 or CDCl3
on a Bruker spectrometer. Elemental analyses were
performed on a CHNꢀOꢀRapid instrument and were
within ± 0.4 % of the theoretical values.
General Procedure for the Preparation of TCA
derivatives 1-12. A mixture of Lꢀcysteine (0.121 g,
1.0 mmol) and appropriate aldehyde (1.0 mmol) in
ethanol (25 mL) was stirred at room temperature for 8
h, and the solid separated was collected, washed with
diethyl ether and dried to obtain 1-12.
4.1.6
(4R)-2-(4-fluorophenyl)thiazolidine-4-carboxylic
acid (6) yield 82%. 1H NMR(300 MHz, DMSOꢀd6) δ
7.62ꢀ7.47 (m, 2H), 7.24ꢀ7.14 (m, 2H), 5.68 (s, 0.6H),
5.52 (s, 0.4H), 4.24ꢀ4.20 (m, 0.6H), 3.93ꢀ3.88 (m,
0.4H), 3.41ꢀ3.29 (m, 1H), 3.17ꢀ3.07 (m, 1H). MS (ESI)
m/z 226 (Mꢀ1). Anal. Calcd for C10H10FNO2S: C,
52.85; H, 4.44; N, 6.16; Found: C, 52.99; H, 4.42; F,
8.36; N, 6.19.
4.1.7
(4R)-2-(2-chlorophenyl)thiazolidine-4-carboxylic
acid (7) yield 83%. 1H NMR(300 MHz, DMSOꢀd6) δ
7.84ꢀ7.83 (m, 0.3H), 7.58ꢀ7.55 (m, 0.8H), 7.45ꢀ7.22
(m, 3H), 5.96 (s, 0.7H), 5.77 (s, 0.3H), 4.19ꢀ4.15 (m,
0.7H), 4.00ꢀ3.95 (m, 0.3H), 3.38ꢀ3.22 (m, 1H),
3.16ꢀ2.94 (m, 1H). MS (ESI) m/z 242 (Mꢀ1). Anal.
Calcd for C10H10ClNO2S: C, 49.28; H, 4.14; N, 5.75;
Found: C, 49.46; H, 4.17; N, 5.78.
4.1.1(4R)-2-phenylthiazolidine-4-carboxylic acid (1)
yield 84%. 1H NMR(300 MHz, DMSOꢀd6)
δ
7.53ꢀ7.24 (m, 5H), 5.68 (s, 0.5H), 5.50 (s, 0.5H),
4.26ꢀ4.22 (m, 0.5H), 3.93ꢀ3.88 (m, 0.5H), 3.41ꢀ3.27
(m, 1H), 3.17ꢀ3.05 (m, 1H). MS (ESI) m/z 210 (M+1).
Anal. Calcd for C10H11NO2S: C, 57.39; H, 5.30; N,
6.69. Found: C, 57.62; H, 5.28; N, 6.71.
4.1.2
4.1.8
(4R)-2-(4-hydroxyphenyl)thiazolidine-4-carboxyl
ic acid (2) yield 87%. 1H NMR(300 MHz, DMSOꢀd6)
δ 7.32ꢀ7.23 (m, 2H), 6.75ꢀ6.69 (m, 2H), 5.53 (s, 0.5H),
5.39 (s, 0.5H), 4.27ꢀ4.23 (m, 0.5H), 3.86ꢀ3.81 (m,
0.5H), 3.37ꢀ3.24 (m, 1H), 3.17ꢀ3.01 (m, 1H). MS (ESI)
m/z 226 (M+1). Anal. Calcd for C10H11NO3S: C,
53.32; H, 4.92; N, 6.22. Found: C, 53.50; H, 4.94; N,
6.20.
(4R)-2-(3-chlorophenyl)thiazolidine-4-carboxylic
acid (8) yield 81%. 1H NMR(300 MHz, DMSOꢀd6) δ
7.66ꢀ7.34 (m, 4H), 5.71 (s, 0.6H), 5.53 (s, 0.4H),
4.20ꢀ4.17 (m, 0.6H), 3.94ꢀ3.88 (m, 0.4H), 3.39ꢀ3.29
(m, 1H), 3.15ꢀ3.07 (m, 1H). MS (ESI) m/z 242 (Mꢀ1).
Anal. Calcd for C10H10ClNO2S: C, 49.28; H, 4.14; N,
5.75; Found: C, 49.54; H, 4.16; N, 5.77.
4.1.9
4.1.3
(4R)-2-(4-chlorophenyl)thiazolidine-4-carboxylic
(4R)-2-(2-methoxyphenyl)thiazolidine-4-carboxy
lic acid (3) yield 82%. 1H NMR(300 MHz, DMSOꢀd6)
δ 7.51ꢀ7.19 (m, 2H), 7.03ꢀ6.89 (m, 2H), 5.85 (s, 0.6H),
5.68 (s, 0.4H), 4.18ꢀ4.13 (m, 0.6H), 3.87ꢀ3.84 (m,
0.4H), 3.79+3.78 (s, 3H), 3.36ꢀ3.15 (m, 1H), 2.99ꢀ2.93
(m, 1H). MS (ESI) m/z 240 (M+1). Anal. Calcd for
C11H13NO3S: C, 55.21; H, 5.48; N, 5.85; Found: C,
55.51; H, 5.46; N, 5.87.
1
acid (9) yield 78%. H NMR(300 MHz, DMSOꢀd6) δ
7.55ꢀ7.53 (m, 1H), 7.46ꢀ7.35 (m, 3H), 5.69 (s, 0.6H),
5.50 (s, 0.4H), 4.19ꢀ4.15 (m, 0.6H), 3.92ꢀ3.86 (m,
0.4H), 3.38ꢀ3.26 (m, 1H), 3.13ꢀ3.04 (m, 1H). MS (ESI)
m/z 242 (Mꢀ1). Anal. Calcd for C10H10ClNO2S: C,
49.28; H, 4.14; N, 5.75; Found: C, 49.60; H, 4.12; N,
5.77.
4.1.10
4.1.4
(4R)-2-(2-bromophenyl)thiazolidine-4-carboxylic
acid (10) yield 73%. 1H NMR(300 MHz, DMSOꢀd6) δ
7.84ꢀ7.54 (m, 2H), 7.54ꢀ7.34 (m, 1H), 7.27ꢀ7.14 (m,
1H), 5.90 (s, 0.7H), 5.72 (s, 0.3H), 4.20ꢀ4.16 (m,
0.7H), 4.00ꢀ3.95 (m, 0.3H), 3.37ꢀ3.21 (m, 1H),
3.08ꢀ2.93 (m, 1H). MS (ESI) m/z 286 (Mꢀ1). Anal.
Calcd for C10H10BrNO2S: C, 41.68; H, 3.50; N, 4.86;
Found: C, 41.87; H, 3.48; N, 4.88.
(4R)-2-(4-methoxyphenyl)thiazolidine-4-carbox
ylic acid (4) yield 81%. 1H NMR(300 MHz,
DMSOꢀd6) δ 7.45ꢀ7.35 (m, 2H), 6.93ꢀ6.86 (m, 2H),
5.59 (s, 0.5H), 5.44 (s, 0.5H), 4.26ꢀ4.22 (m, 0.5H),
3.88ꢀ3.83 (m, 0.5H), 3.74+3.73 (s, 3H), 3.38ꢀ3.25 (m,
1H), 3.17ꢀ3.03 (m, 1H). MS (ESI) m/z 240 (M+1).
Anal. Calcd for C11H13NO3S: C, 55.21; H, 5.48; N,
5.85. Found: C, 55.43; H, 5.50; N, 5.83.
4.1.11
4.1.5
(4R)-2-(4-bromophenyl)thiazolidine-4-carboxylic
acid (11) yield 87%. 1H NMR(300 MHz, DMSOꢀd6) δ
7.58ꢀ7.38 (m, 4H), 5.68 (s, 0.6H), 5.50 (s, 0.4H),
4.19ꢀ4.15 (m, 0.6H), 3.93ꢀ3.88 (m, 0.4H), 3.39ꢀ3.35
(4R)-2-(3-fluorophenyl)thiazolidine-4-carboxylic
acid (5) yield 87%. 1H NMR(300 MHz, DMSOꢀd6) δ
7.42ꢀ7.24 (m, 3H), 7.17ꢀ7.05 (m, 1H), 5.69 (s, 0.6H),
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(m, 1H), 3.14ꢀ3.035 (m, 1H). MS (ESI) m/z 286 (Mꢀ1).
6.85ꢀ6.84 (d, 2H), 5.95 (s, 1H), 4.83 (s, 1H), 3.77 (s,
Anal. Calcd for C10H10BrNO2S: C, 41.68; H, 3.50; N,
4.86. Found: C, 41.51; H, 3.52; N, 4.88.
4.1.12
3H), 3.38ꢀ3.31 (m, 2H), 1.27 (s, 9H). MS (ESI) m/z
338 (Mꢀ1). Anal. Calcd for C16H21NO5S: C, 56.62; H,
6.24; N, 4.13. Found: C, 56.90; H, 6.21; N, 4.17.
4.1.17
(4R)-2-(5-fluoro-2-hydroxyphenyl)thiazolidine-4-
1
carboxylic acid (12) yield 84%. H NMR(300 MHz,
(2R,4R)-3-(tert-butoxycarbonyl)-2-(3-fluorophen
1
DMSOꢀd6) δ 9.89 (b, 0.6H), 7.32ꢀ7.27 (m, 0.4H),
7.16ꢀ7.12 (m, 0.6H), 7.01ꢀ6.87 (m, 1H), 6.84ꢀ6.75 (m,
1H), 5.84 (s, 0.6H), 5.66 (s, 0.4H), 4.22ꢀ4.18 (m,
0.6H), 3.90ꢀ3.85 (m, 0.4H), 3.26ꢀ3.260 (m, 1H),
3.05ꢀ2.98 (m, 1H). MS (ESI) m/z 242 (Mꢀ1). Anal.
Calcd for C10H10FNO3S: C, 49.37; H, 4.14; N, 5.76.
Found: C, 49.56; H, 4.12; N, 5.74.
yl)thiazolidine-4-carboxylic acid (17) yield 77%. H
NMR(300 MHz, DMSOꢀd6) δ 7.64ꢀ7.57 (m, 1H),
7.43ꢀ7.31 (m, 2H), 7.10,ꢀ7.05 (m, 1H), 6.13+5.97 (2s,
1H), 4.72ꢀ4.52 (m, 1H), 3.49ꢀ3.43 (m, 1H), 3.20ꢀ3.03
(m, 1H), 1.35+1.12 (2s, 9H). MS (ESI) m/z 326 (Mꢀ1).
Anal. Calcd for C15H18FNO4S: C, 55.03; H, 5.54; N,
4.28; Found: C, 55.35; H, 5.56; N, 4.26.
General Procedure for the Preparation of TBTCA
derivatives 13-24. A mixture of TCA (1.0 mmol) and
appropriate NaOH (10%, 1.0 mmol) in dioxane (25
mL) was stirred at iceꢀwater temperature for 2 h.
BOC2O (1.0 mmol) was added and stirred at iceꢀwater
temperature for 1 h and then room temperature for 5 h.
Most of Solvent was extracted and appropriate amount
of water was added to adjust to neutral pH values.
Ethyl acetate was added and extracted (50 mL×3), and
washed with appropriate saturated aqueous solution of
common salt, and dried with anhydrous magnesium
sulphate. Solvent was extracted to dry to obtain whiter
solids 13ꢀ24.
4.1.18
(2R,4R)-3-(tert-butoxycarbonyl)-2-(4-fluorophen
yl)thiazolidine-4-carboxylic acid (18) yield 75%. H
1
NMR(300 MHz, CD2Cl2) δ 8.80 (bs, 1H), 7.59 (s, 2H),
7.04 (t, 2H), 5.96 (s, 1H), 4.94 (s, 1H), 3.37 (s, 1H),
1.25 (s, 9H). MS (ESI) m/z 326 (Mꢀ1). Anal. Calcd for
C15H18FNO4S: C, 55.03; H, 5.54; N, 4.28; Found: C,
55.33; H, 5.52; N, 4.30.
4.1.19
(2R,4R)-3-(tert-butoxycarbonyl)-2-(2-chlorophen
yl)thiazolidine-4-carboxylic acid (19) yield 80%. H
1
NMR(300 MHz, CD2Cl2) δ 8.29 (b, 1H), 7.32ꢀ7.29 (m,
2H), 7.22ꢀ7.16 (m, 2H), 6.26 (s, 1H), 4.78ꢀ4.77 (m,
1H), 3.34ꢀ3.33 (m, 2H), 1.21 (s, 9H). MS (ESI) m/z
342 (Mꢀ1). Anal. Calcd for C15H18ClNO4S: C, 52.40;
H, 5.28; N, 4.07; Found: C, 52.40; H, 5.28; N, 4.07.
4.1.20
4.1.13
(2R,4R)-3-(tert-butoxycarbonyl)-2-phenylthiazol
idine-4-carboxylic acid (13) yield 78%. 1H NMR(300
MHz, DMSOꢀd6+CDCl3)
δ 7.56ꢀ7.53 (d, 2H),
7.24ꢀ7.14 (m, 3H), 6.04+5.85 (2s, 1H), 4.75ꢀ4.57 (d,
1H), 3.23ꢀ3.16 (m, 2H), 1.34+1.10 (2s, 9H). MS (ESI)
m/z 308 (Mꢀ1). Anal. Calcd for C15H19NO4S: C, 58.23;
H, 6.19; N, 4.53. Found: C, 58.05; H, 6.15; N, 4.57.
4.1.14
(2R,4R)-3-(tert-butoxycarbonyl)-2-(4-hydroxyph
enyl)thiazolidine-4-carboxylic acid (14) yield 76%.
1H NMR(300 MHz, DMSOꢀd6) δ 9.35 (b, 1H),
7.42ꢀ7.39 (d, 2H), 6.68ꢀ6.65 (d, 2H), 6.01+5.84 (2s,
1H), 4.67ꢀ4.51 (m, 1H), 3.44ꢀ3.37 (m, 1H), 3.15ꢀ3.05
(m, 1H), 1.34+1.12 (2s, 9H). MS (ESI) m/z 324 (Mꢀ1).
Anal. Calcd for C15H19NO5S: C, 55.37; H, 5.89; N,
4.30. Found: C, 55.62; H, 6.85; N, 4.32.
(2R,4R)-3-(tert-butoxycarbonyl)-2-(3-chlorophen
yl)thiazolidine-4-carboxylic acid (20) yield 81%. H
1
NMR(300 MHz, DMSOꢀd6)
δ 13.12 (b, 1H),
7.83ꢀ7.79 (d, 1H), 7.59ꢀ7.57 (d, 1H), 7.39ꢀ7.34 (t, 2H),
6.14+5.98 (2s, 1H), 4.75ꢀ4.56 (m, 1H), 3.52ꢀ3.46 (m,
1H), 3.22ꢀ3.05 (m, 1H), 1.38ꢀ1.14 (2s, 9H). MS (ESI)
m/z 342 (Mꢀ1). Anal. Calcd for C15H18ClNO4S: C,
52.40; H, 5.28; N, 4.07; Found: C, 52.63; H, 5.26; N,
4.09.
4.1.21
(2R,4R)-3-(tert-butoxycarbonyl)-2-(4-chlorophen
1
yl)thiazolidine-4-carboxylic acid (21) yield 73%. H
NMR(300 MHz, DMSOꢀd6)
δ 13.08 (b, 1H),
4.1.15
7.67ꢀ7.64 (d, 2H), 7.39ꢀ7.37 (d, 2H), 6.11+5.96 (2s,
1H), 4.71ꢀ4.56 (m, 1H), 3.49ꢀ3.43 (m, 1H), 3.36 (m,
1H), 3.17ꢀ3.03 (m, 1H),1.34+1.12 (2s, 9H). MS (ESI)
m/z 342 (Mꢀ1). Anal. Calcd for C15H18ClNO4S: C,
52.40; H, 5.28; N, 4.07; Found: C, 52.16; H, 5.30; N,
4.05.
(2R,4R)-3-(tert-butoxycarbonyl)-2-(2-methoxyph
enyl)thiazolidine-4-carboxylic acid (15) yield 84%.
1H NMR(300 MHz, CDCl3+TMS) δ 7.83ꢀ7.60 (m,
1H), 7.277 (m, 1H), 7.26ꢀ7.23 (m, 1H), 6.98ꢀ6.85 (m,
1H), 6.38+6.29 (2s, 1H), 4.84ꢀ4.71 (m, 1H), 3.86 (s,
3H), 3.40ꢀ3.26 (m, 2H), 1.42+1.23 (2s, 9H). MS (ESI)
m/z 338 (Mꢀ1). Anal. Calcd for C16H21NO5S: C, 56.62;
H, 6.24; N, 4.13; Found: C, 56.85; H, 6.22; N, 4.15.
4.1.16
4.1.22
(2R,4R)-2-(2-bromophenyl)-3-(tert-butoxycarbo
nyl)thiazolidine-4-carboxylic acid (22) yield 84%.
1H NMR(300 MHz, DMSOꢀd6) δ 13.19 (b, 0.5H),
8.24ꢀ8.15 (m, 1H), 7.63ꢀ7.56 (m, 1H), 7.40ꢀ7.39 (m,
1H), 7.24ꢀ7.19 (m, 1H), 6.12 (s, 1H), 4.69ꢀ4.52 (m,
1H), 3.54ꢀ3.44 (m, 1H), 3.18ꢀ2.98 (m, 1H), 1.35+1.10
(2R,4R)-3-(tert-butoxycarbonyl)-2-(4-methoxyph
enyl)thiazolidine-4-carboxylic acid (16) yield 80%.
1H NMR(300 MHz, CD2Cl2) δ 7.45ꢀ7.44 (d, 2H),
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(2s, 9H). MS (ESI) m/z 386 (Mꢀ1). Anal. Calcd for
and applied to microtitration plates with serially
C15H18BrNO4S: C, 46.40; H, 4.67; N, 3.61; Found: C,
46.66; H, 4.69; N, 3.59.
4.1.23
diluted compounds in DMSO to be tested and
incubated at 37 oC for 24 h. After the IC50s were
visually determined on each of the microtitration
plates, 50 mL of PBS (phosphate buffered saline 0.01
mol/L, pH 7.4, Na2HPO4·12H2O (2.9 g), KH2PO4 (0.2
g), NaCl (8.0 g), KCl (0.2 g), distilled water (1000 mL)
containing 2 mg of MTT/mL was added to each well.
Incubation was continued at room temperature for 4−5
h. The content of each well was removed, and 100 mL
of isopropanol containing 5% 1 mol/L HCl was added
to extract the dye. After 12 h of incubation at room
temperature, the optical density (OD) was measured
with a microplate reader at 570 nm. The observed
IC50s are presented in Table 4.
(2R,4R)-2-(4-bromophenyl)-3-(tert-butoxycarbo
nyl)thiazolidine-4-carboxylic acid (23) yield 78%.
1H NMR(300 MHz, DMSOꢀd6) δ 13.07 (b, 0.5H),
7.60ꢀ7.58 (d, 2H), 7.52ꢀ7.50 (d, 2H), 6.09+5.95 (2s,
1H), 4.70ꢀ4.54 (m, 1H), 3.48ꢀ3.42 (m, 1H), 3.17ꢀ3.03
(m, 1H), 1.34+1.12 (2s, 9H). MS (ESI) m/z 386 (Mꢀ1).
Anal. Calcd for C15H18BrNO4S: C, 46.40; H, 4.67; N,
3.61. Found: C, 46.72; H, 4.49; N, 3.66.
4.1.24
(2R,4R)-3-(tert-butoxycarbonyl)-2-(5-fluoro-2-hy
droxyphenyl)thiazolidine-4-carboxylic acid (24)
yield 75%. 1H NMR(300 MHz, DMSOꢀd6)
δ
7.80ꢀ7.76 (m, 1H), 6.91ꢀ6.84 (m, 1H), 6.76 (m, 1H),
6.08 (s, 1H), 4.61ꢀ4.45 (m, 1H), 3.45ꢀ3.39 (m, 1H),
3.11ꢀ2.96 (m, 1H), 1.35+1.15 (2s, 9H). MS (ESI) m/z
342 (Mꢀ1). Anal. Calcd for C15H18FNO5S: C, 52.47; H,
5.28; N, 4.08. Found: C, 52.11; H, 5.25; N, 4.12.
Acknowledgments
This work was supported by the National Natural
Science Foundation of China (No. 21202153) and
Foundation of Zhejiang Educational Committee (No.
Y201223263). We also thank Dr. Zhe Li (Department
of Chemistry, Tsinghua University, Beijing) for the
help of the theoretical model calculation.
4.2 Crystallographic studies
Xꢀray singleꢀcrystal diffraction data for ‘2R, 4R’
isomer of compounds 13, 15, 21 and 22 were collected
on a Nonius CAD4 diffractometer equipped with
graphiteꢀmonochromatized MoKα (λ = 0.71073 Å)
radiation. The program CAD4 software was used for
data collection and cell refinement. Data reduction
was solved by XCAD4 program. Structure was solved
by direct methods using the SHELXS program of the
SHELXTL package and refined by fullꢀmatrix
leastꢀsquares methods with SHELXL19. All
nonꢀhydrogen atoms of ‘2R, 4R’ isomer of compounds
13, 15, 21 and 22 were refined with anisotropic
thermal parameters. All hydrogen atoms were placed
in geometrically idealized positions and constrained to
ride on their parent atoms.
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